Benzopyran intermediates

ABSTRACT

A compound of the following formula: ##STR1## wherein: R 1  and R 2  is hydrogen or C 1-4  alkyl or R 1  and R 2  together are C 2-5  polymethylene; R 3  is hydroxy, C 1-6  alkoxy or C 1-7  alkylcarbonyloxy; R&#39; 4  is ethyl, isopropyl, t-butyl or cyclopentyl, and R 1   6  is hydrogen or C 1-6  alkyl.

CROSS-REFERENCE

This is a division of Ser. No. 447,002 filed Dec. 6, 1989, which is adivisional application of Ser. No. 045,626 filed May 1, 1987, now U.S.Pat. No. 4,943,582, issued Jul. 24, 1990.

The present invention relates to novel benzopyrans havingpharmacological activity, to a process and intermediates for preparingthem, to pharmaceutical compositions containing them, and to their usein the treatment of mammals.

European Patent Publications 76075, 93535, 95316, 107423, 120427,126311, 126350, 126367 and 138134 disclose classes of compounds that aredescribed as having blood pressure lowering activity oranti-hypertensive activity.

A class of compounds has now been discovered which are 4-substitutedbenzopyrans substituted in the 6-position by an alkyl group. Inaddition, such benzopyrans have been found to have blood pressurelowering activity, useful in the treatment of hypertension. In addition,these compounds are believed to be K⁺ channel activators which indicatesthat they are of potential use in the treatment of disorders associatedwith smooth muscle contraction of the gastro-intestinal tract,respiratory system, uterus or urinary tract. Such disorders includeirritable bowel syndrome and diverticular disease, reversible airwaysobstruction and asthma; premature labour; and incontinence. They arealso indicated as of potential use in the treatment of cardiovasculardisorders other than hypertension, such as congestive heart failure,angina, peripheral vascular disease and cerebral vascular disease.

Accordingly, the present invention provides a compound of formula (I)or, when the compound of formula (I) contains a salifiable group, apharmaceutically acceptable salt thereof: ##STR2## wherein: Y is N or(when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy) CH;

one of R₁ and R₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkylor R₁ and R₂ together are C₂₋₅ -polymethylene;

R₃ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy;

R₄ is a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group optionallysubstituted by a group R₇ which is hydroxy, C₁₋₆ alkoxy, aminooptionally substituted by one or two C₁₋₆ alkyl groups; C₁₋₇alkanoylamino, C₃₋₈ -cycloalkyloxy, C₃₋₈ cycloalkylamino, or1,3-dioxo-2-isoindoline;

When Y is N, R₅ is hydrogen, C₁₋₆ alkyl optionally substituted byhalogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or aminooptionally substituted by one or two independent C₁₋₆ alkyl groups, orC₂₋₆ alkenyl, amino optionally substituted by a C₁₋₆ alkyl, C₃₋₈cycloalkyl or C₁₋₆ alkenyl group or by a C₁₋₆ alkanoyl group optionallysubstituted by up to three halo atoms, by a phenyl group optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, or aryl orheteroaryl, either being optionally substituted by one or more groups oratoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy,halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or aminoor aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groupsand R₆ is hydrogen or C₁₋₆ alkyl, or R₅ and R₆ together are --CH₂--(CH₂)_(n) --Z--(CH₂)_(m) --wherein m and n are 0 to 2 such that m+n is1 or 2 and Z is CH₂, O, S or NR wherein R is hydrogen, C₁₋₉ alkyl, C₂₋₇alkanoyl, phenyl C₁₋₄ --alkyl, naphthylcarbonyl, phenylcarbonyl orbenzyl-carbonyl optionally substituted in the phenyl or naphthyl ring byone or two of C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; mono- or bi-cyclic-heteroarylcarbonyl;

When Y is CH, R₅ is NR₈ R₉ wherein R₈ and R₉ are independently C₁₋₆alkyl, R₈ is hydrogen and R₉ is C₁₋₆ alkyl or R₈ and R₉ together areC₄₋₅ polymethylene; or R₆ and R₈ together are --(CH₂)_(p) --wherein p is2 or 3, and R₉ is hydrogen or C₁₋₆ alkyl; or R₅ is CH₂ R₁₀ wherein R₁₀is hydrogen or C₁₋₅ alkyl; or R₆ and R₁₀ are --(CH₂)_(q) --wherein q is2 or 3;

X is oxygen or sulphur; or

R₅, R₆, X and Y (when N) together are tetrahydroisoquinolinone ortetrahydroisoquinolinthione, optionally substituted in the phenyl ringas defined for R above;

the nitrogen-containing group in the 4-position being trans to the R₃group when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy.

Y is preferably N.

Preferably, R₁ and R₂ are both C₁₋₄ alkyl, in particular both methyl.

When R₃ is C₁₋₆ alkoxy, preferred examples of R₃ include methoxy andethoxy, of which methoxy is more preferred. When R₃ is C₁₋₇ acyloxy apreferred class or R₃ is unsubstituted carboxylic acyloxy, such asunsubstituted aliphatic acyloxy. However, it is more preferred that R₃is hydroxy.

Examples of R₄ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, methyl, ethyl, n-and iso-propyl, n-, iso-, sec- andtert-butyl, optionally substituted by a group R₇ ¹ which is hydroxy,C₁₋₄ alkoxy, amino optionally substituted by one or two C₁₋₄ alkylgroups, C₁₋₅ alkanoylamino, C₅₋₇ cycloalkyloxy or C₅₋₇ cycloalkyl. C₁₋₄alkyl groups in H₇ ¹ may be methyl, ethyl, n- or iso- propyl, n-,iso-sec-, or tert-butyl. C₅₋₇ cycloalkyl groups in R₇ ¹ may becyclopentyl, cyclohexyl or cycloheptyl. R₄ is preferably C₅₋₇ cycloalkylor C₁₋₄ alkyl.

When Y is N:

Examples of R₅, when C₁₋₆ alkyl, include methyl, ethyl and n- andiso-propyl. Preferably such R₅ is methyl.

A sub-group of R₅, when C₁₋₆ alkyl substituted by halogen is C₁₋₆ alkylsubstituted by chloro or bromo.

Examples thereof include methyl or ethyl terminally substituted bychloro or bromo.

Examples of R₅, when C₁₋₆ alkyl substituted by hydroxy, include methylor ethyl terminally substituted by hydroxy.

A sub-group of R₅, when C₁₋₆ alkyl substituted by alkoxy is C₁₋₆ alkylsubstituted by methoxy or ethoxy. Examples thereof include methyl orethyl terminally substituted by methoxy or ethoxy.

A sub-group of R₅, when C₁₋₆ alkyl substituted by C₁₋₆ alkoxycarbonyl isC₁₋₆ alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examplesthereof include methyl or ethyl terminally substituted bymethoxycarbonyl or ethoxycarbonyl.

Examples of R₅, when C₁₋₆ alkyl substituted by carboxy include methyl orethyl terminally substituted by carboxy.

Examples of R₅ when alkyl substituted by amino optionally substituted byone or two independent C₁₋₆ alkyl groups include a group (CH₂)_(r)NR_(a) R_(b) where r is 1 to 6, and R_(a) and R_(b) are eachindependently hydrogen or C₁₋₆ alkyl. Examples of r include 1 and 2, inparticular 1. Preferably R_(a) and R_(b) are each independently selectedfrom hydrogen and methyl. Examples of R₅, when C₂₋₆ alkenyl includevinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl,but-3-enyl, 1-methylenepropyl, or 1-methylprop-2-enyl, in both their Eand Z forms where stereoisomerism exists.

Examples of R₅ when amino optionally substituted as hereinbefore definedinclude amino optionally substituted by a C₁₋₄ alkyl group as describedfor R₇ ¹, an allyl or trichloroacetyl group or by a phenyl groupoptionally substituted by one methyl, methoxy or chloro group or atom,in particular amino, methylamino, and phenylamino optionally substitutedin the phenyl ring by one methyl, methoxy or chloro group or atom.

Examples of R₅ when aryl include phenyl and naphthyl, of which phenyl ispreferred.

A sub-group of R₅ heteroaryl or heteroaryl in a Z moiety when NR is 5-or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ofwhich 5- or 6-membered monocyclic heteroaryl is preferred. In addition,5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroarylpreferably contains one, two or three heteroatoms which are selectedfrom the class of oxygen, nitrogen and sulphur and which, in the case ofthere being more than one heteroatom, are the same or different.

Examples of 5- or 6-membered monocyclic heteroaryl containing one, twoor three heteroatoms which are selected from the class of oxygen,nitrogen and sulphur include furyl, thienyl, pyrryl, oxazolyl,thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl,pyrimidyl, pyrazyl and triazyl. Preferred examples of such groupsinclude furanyl, thienyl, pyrryl and pyridyl, in particular 2- and3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4-pyridyl.

Examples of 9- or 10-membered bicyclic heteroaryl containing one, two orthree heteroatoms which are selected from the class of oxygen, nitrogenand sulphur include benzofuranyl, benzothienyl, indolyl and indazolyl,quinolyl and isoquinolyl, and quinazonyl. Preferred examples of suchgroups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and3-indolyl, and 2- and 3-quinolyl.

Preferably, the number of groups or atoms for optional substitution ofaryl or heteroaryl is one, two, three or four.

Preferred examples of the groups or atoms for optional substitution ofaryl or heteroaryl include methyl, methoxy, hydroxy, bromo, chloro,fluoro, nitro or cyano.

A sub-group of R₅ is phenyl or naphthyl or a 5- or 6-membered monocyclicor a 9- or 10-membered bicyclic heteroaryl, the phenyl, naphthyl orheteroaryl group being optionally substituted by one, two, three or fourgroups or atoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen, (such as chloro, bromo or, in particular, fluoro),trifluoromethyl, nitro or cyano.

A preferred subgroup of phenyl optionally substituted as hereinbeforedefined is phenyl, 4-substituted phenyl, 3-substituted phenyl,3,4-disubstituted phenyl and 3,4,5-trisubstituted phenyl.

A preferred sub-group of 5- or 6-membered monocyclic or 9- or10-membered bicyclic heteroaryl optionally substituted as hereinbeforedefined is unsubstituted or mono-substituted 5- or 6-membered monocyclicor 9- or 10-membered bicyclic heteroaryl, in particular unsubstituted 5-or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl.

R₅ and R₆, when together are --CH₂ --(CH₂)_(n) --Z--(CH₂)_(m) -- asdefined the resulting radical substituting the benzopyran in the4-position is preferably either pyrrolidonyl or piperidonyl.

When Z is other than CH₂, m is often 0 or 1 and n is often 0 or 1.Suitable examples of R when Z is NR include hydrogen, methyl, ethyl, n-and iso-propyl, n-, iso-, sec- and tert- butyl, benzyl, phenylcarbonylor benzylcarbonyl optionally substituted in the phenyl ring by methyl,methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl,pyrrolylcarbonyl or indolylcarbonyl. Preferably R is hydrogen, methyl,n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl orfurylcarbonyl. Most preferably R is methyl.

Preferred examples of R₅ and R₆ are R₅ methyl and R₆ hydrogen and R₅ andR₆ together are C₃ or C₄ polymethylene.

When Y is CH, R₆ is preferably hydrogen and R₅ is NR₈ R₉. Examples of R₈and R₉, include hydrogen (for R₈), methyl, ethyl, n- and iso-propyl, andn-, iso-, sec- and t-butyl, C₄ or C₅ polymethylene or R₈ together withR₆ is --(CH₂)₂ -- or --(CH₂)₃ --, and R₉ is hydrogen or an alkyl groupas described above. Preferably R₈ and R₉ are each methyl or R₆ CHCXNR₈R₉ forms a pyrrolidone or piperidone ring and R₉ is methyl.

Preferably, X is oxygen.

Examples of a pharmaceutically acceptable salt of a compound of formula(I), when the compound contains a salifiable group which is anoptionally substituted amino group, include acid addition salts such asthe hydrochloride and hydrobromide salts. Such a salifiable group may bewithin an R₄ or R₅ group. A carboxy group within R₅ may also be salifiedto form metal salts, such as alkali metal salts, or optionallysubstituted ammonium salts.

The compounds of formula (I) may also exist as hydrates and these areincluded wherever a compound of formula (I) or a salt thereof is hereinreferred to.

The compounds of formula (I), are asymmetric, and, therefore, can existin the form of optical isomers. The present invention extends to allsuch isomers individually and as mixtures, such as racemates.

Examples of compounds of formula (I) include the compounds prepared inthe Examples hereinafter.

The present invention also provides a process for the preparation of acompound of formula (I) or, when the compound of formula (I) contains asalifiable group, a pharmaceutically acceptable salt thereof, whichcomprises;

i) (When Y is N) acylating a compound of formula (II): ##STR3## whereinR₄ ' is R₄ or a group convertible thereto; R₁ R₂ and R₃ are ashereinbefore defined, and R₆ ¹ is hydrogen or C₁₋₆ alkyl, the R₆ ¹ NHgroup being trans to the R₃ group,

a) with an acylating agent of formula (III):

    R.sub.11 --CO--L.sub.1                                     (III)

wherein L₁ is a leaving group, and R₁₁ is hydrogen, C₁₋₆ alkyloptionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, carboxy or amino optionally substituted as hereinbeforedefined for R₅, C₂₋₆ alkenyl or optionally substituted aryl orheteroaryl as hereinbefore defined for R₅, or a group convertible to R₅as hereinbefore defined, and thereafter, when R₆ is hydrogen and R₁₁ isQ(CH₂)_(z) --, where z is 3 or 4; and Q is a leaving group, cyclisingthe resultant compound;

b) with a compound of formula (IV)

    X═C═N.R.sub.12                                     (IV)

wherein R₁₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkanoyloptionally substituted by up to three halo atoms, or phenyl optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; and X is oxygen orsulphur, and thereafter when R₁₂ is hydrogen, optionally converting R₁₂; or

ii) where, in the resultant compound of formula (I), Y is N and R₅ andR₆ are joined together, or Y is CH, reacting a compound of formula (V):##STR4## wherein R₄ ', R₁ and R₂ are as hereinbefore defined, with acompound of formula (VI):

    R.sub.14 YHCOR.sub.13                                      (VI)

or an anion thereof (when Y is CH); wherein (when Y is N), R₁₃ and R₁₄together are --CH₂ --(CH₂)_(n) --Z--(CH₂)_(m) -- or R₁₄ YHCOR₁₃ istetrahydroisoquinolinone; or (when Y is CH) R₁₃ is NR₈ 'R₉ or CHR₁₀ CO₂R₁₅ wherein R₁₅ is C₁₋₆ alkyl or benzyl, R₈ ' is R₈ or an aminoprotecting group and the remaining variables are as hereinbeforedefined; and thereafter, if necessary, converting R₁₃ to R₇, convertingR₈ ' to R₈ ; optionally converting R₃ in the resulting compound intoanother R₃ ; converting R₄ ' to R₄ and optionally thiating the R₆--Y--CO--R₅ group in the resulting compound to give a compound wherein Xis sulphur; and when the resulting compound of formula (I) contains asalifiable group, optionally forming a pharmaceutically acceptable saltthereof.

In the process variant i) a) acylation of a compound of formula (II)with an acylating agent of formula (III), the leaving group L₁ is agroup that is displaceable by a primary or secondary amino nucleophile.Examples of such a group include C₁₋₄ alkanoyloxy, and halogen, such aschloro and bromo. When the leaving group L₁ is either of these examples,the acylating agent of formula (III) is either an acid anhydride or anacid halide. When it is an acid anhydride, it may be a mixed or simpleanhydride. If it is a mixed anhydride, it may be prepared in situ from acarboxylic acid and an acid halide, although this is less preferred thanusing the halide itself.

In process variant i) a), when R₅ in the desired compound of formula (I)is an R₅ optionally substituted amino-substituted alkyl group ashereinbefore defined, it is preferred that R₁₁ is a group convertible tothe R₅ substituted alkyl group as hereinbefore defined, in particularthat it is C₁₋₆ alkyl substituted by halo, especially bromo. The R₁₁halo substituent in the resultant compound of process variant i) a) maybe converted to an R₅ substituent which is amino optionally substitutedas hereinbefore defined by a conventional amination reaction withammonia or a corresponding alkyl- or dialkylamine.

Less favourably R₁₁ may be C₁₋₆ alkyl substituted by protected amino,protected C₁₋₆ alkylamino or amino substituted by two independent C₁₋₆alkyl groups, it being necessary to protect the R₁₁ amino function inprocess variant i) a).

When the acylating agent of formula (III) is an acid anhydride, theacylation of the compound of formula (II) may be carried out in thepresence of an acid acceptor, such as sodium acetate, optionally usingthe anhydride as the solvent.

When the acylating agent of formula (III) is an acid halide, theacylation of the compound of formula (II) is, preferably, carried out ina non-aqueous medium, such as dichloromethane, in the presence of anacid acceptor, such as triethylamine, trimethylamine, pyridine, picolineor calcium, potassium or sodium carbonate.

When R₃ in a compound of formula (II) is hydroxy, there is a risk of aside-reaction between the hydroxy group and the acylating agent offormula (III). However, the reaction may be carried out under controlledconditions such that only the R₆ ¹ YH-- is acylated, for example, byusing a C₂₋₉ acyloxy group as the leaving group L₁, in the acylatingagent of formula (III) in the manner as previously described for an acidanhydride, and/or effecting the reaction at relatively low temperature,e.g. at below 10° C. Alternatively R₃ may be C₁₋₇ acyloxy in a compoundof formula (II), although less preferably if R₃ in the resultantcompound of formula (I) is to be hydroxy, and, after reaction with theacylating agent of formula (III), be converted into hydroxy, asdescribed hereinafter.

When R₉ is Q(CH₂)_(z) where the variables are as hereinbefore defined,the leaving group Q is a group that is displaceable by a secondary aminonucleophile adjacent to a carbonyl function. A preferred example ischloro.

The cyclisation reaction when R₁₁ is Q(CH₂)_(z) where the variables areas hereinbefore defined is preferably carried out in an inert solventsuch as dimethylformamide.

In process variant i) b), when R₁₂ in a compound of formula (IV) is C₁₋₆alkyl, C₁₋₆ alkanoyl optionally substituted as hereinbefore defined, orphenyl optionally substituted as hereinbefore defined, the reactionbetween the compounds of formulae (II) and (IV) is, preferably, carriedout in a solvent, such as methylene chloride, at below room temperature,in particular below 10° C.

When R₁₂ is hydrogen, the reaction between the compounds of formulae(II) and (IV) is, preferably, carried out using a corresponding alkalimetal cyanate or thiocyanate, for example that of sodium or potassium,in an optionally methanolic aqueous medium acidified with a mineralacid, such as dilute hydrochloric acid. A slightly elevated temperaturesuch as 50° to 90° C. is apt.

In the process variant ii) when Y is N, reaction of a compound offormula (V) with a compound of formula (VI), it is particularlypreferred that the reaction is carried out under basic conditions so asto facilitate the formation of the anion of the compound of formula(VI), for example, in the presence of sodium hydride.

In the process variant ii) when Y is CH, the reaction is preferablycarried out in a solvent such as tetrahydrofuran at a temperature of-70° C. to reflux, depending on the anion of the compound of formula(VI). The anion is generated by use of a base, such as lithiumdiisopropylamide.

An intermediate compound wherein R₁₃ is CHR₁₀ CO₂ R₁₅ may be convertedto a compound of formula (I) wherein R₇ is CH₂ R₁₀, by deesterificationfollowed by decarboxylation.

Deesterification may be effected conventionally, the most appropriatemethod depending to some extent on the nature of the group R₁₄. However,basic reaction conditions will generally be applicable. The processconditions described hereinafter for the decarboxylation in the presenceof base are in general suitable for this deesterification.

When R₁₄ is, for example, a tert-butyl group, deesterification may alsobe effected conventionally in the presence of acid such astrifluoroacetic acid or aqueous hydrochloric acid. Reaction may beeffected at ambient temperature or a slightly higher temperature.

When R₁₄ is for example a benzyl group, deesterification may also beeffected conventionally by hydrogenolysis, for example bytransition-metal catalysed hydrogenation, such as that usingpalladium/charcoal.

The decarboxylation is conveniently effected by treatment with amoderately strong base optionally in an aqueous reaction medium.Examples of bases for the reaction include inorganic bases such assodium hydroxide. Examples of reaction media include water, usually inadmixture with a water-miscible solvent such that the compound issoluble therein. Examples include aqueous alcohols such as aqueousethanol and aqueous polyethers such as aqueous dioxan. Reaction isconveniently effected at a moderately elevated temperature, such as 50°to 150° C., conveniently at the boiling point of the reaction medium.

Alternatively the decarboxylation may be effected by heating to anon-extreme temperature, for example 60° to 150° C. in an inert solvent,such as benzene, toluene or xylene, for example at solvent boilingpoint.

Spontaneous decarboxylation may occur under the reaction conditions forthe deesterification. Even where this is not the case, it is convenientto decarboxylate the CHR₁₀ CO₂ H compound in situ without isolation. Itis especially convenient to carry out the conversion CHR₁₀ CO₂ R₁₂ toCH₂ R₁₀ as a single-step one-pot process, by treatment with a moderatelystrong base optionally in an aqueous reaction medium. Suitableconditions are as hereinbefore described for decarboxylation.

The reaction of the compounds of formulae (II) with (III) or (IV)results in a compound of formula (I) wherein R₃ is hydroxy, C₁₋₆ alkoxyor C₁₋₇ acyloxy, whereas the reaction of the compounds of formulae (V)and (VI) results in a compound of formula (I) wherein R₃ is hydroxy.Examples of an optional conversion of R₃ in a compound of formula (I)into another R₃ are generally known in the art. For example, when R₃ ishydroxy, it may be alkylated using an alkyl iodide in an inert solvent,such as toluene, in the presence of a base, such as potassium hydroxide,or it may be acylated using a carboxylic acid chloride or anhydride in anon-hydroxylic solvent in the presence of antacid acceptor.Alternatively, when R₃ is C₁₋₇ acyloxy or C₁₋₆ alkoxy, it may beconverted into hydroxy by conventional hydrolysis with, for example,dilute mineral acid.

Suitable conversions of R₄ '/R₄ include conventional alkylation oracylation of R₇ when hydroxy or optionally monosubstituted amino. It isusually preferred, however, that such conversions are carried out at anearlier stage.

R₄ ' may be cyano which may be converted to R₄ when a substituted methylgroup, by conventional methods as described in the Examples hereinafter,for example, reduction to give an aminomethyl group.

The optional thiation of the R₆ --Y--CO--R₅ group in a compound offormula (I) to give another compound of formula I, wherein X is sulphur,is, preferably, carried out with conventional thiation agents, such ashydrogen sulphide, phosporous pentasulphide and Lawesson's reagent(p-methoxyphenylthiophosphine sulphide dimer). The use of hydrogensulphide and phosporous pentasulphide may lead to side-reactions and,therefore, the use of Lawesson's reagent is preferred.

The thiation reaction conditions are conventional for the thiation agentemployed. For example, the use of hydrogen sulphide is, preferably, acidcatalysed by, for example, hydrogen chloride in a polar solvent, such asacetic acid or ethanol. The preferred use of Lawesson's reagent is,preferably, carried out under reflux in a dry solvent, such as tolueneor methylene chloride.

The optional formation of a pharmaceutically acceptable salt, when theresulting compound of formula (I) contains a salifiable group, may becarried out conventionally.

A compound of formula (II) wherein R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇acyloxy may be prepared by reacting a compound of formula (V), ashereinbefore defined, with a compound of formula (VII):

    R.sub.6.sup.1 NH.sub.2                                     (VII)

wherein R₆ ¹ is as defined hereinbefore; and optionally converting R₃hydroxyl in the resulting compound of formula (II) into R₃ when C₁₋₆alkoxy or C₁₋₇ acyloxy. The reaction is normally carried out in asolvent, such as a C₁₋₄ alcohol, in particular methanol, ethanol orpropanol at an ambient or an elevated temperature, for example 12° to100° C. The reaction proceeds particularly smoothly if carried out inethanol under reflux.

The resulting compound of formula (II) may be removed from the reactionmixture by removal of the solvent, for example, by evaporation underreduced pressure. Any epoxide impurity may be removed conventionally,for example by chromatography.

The optional conversion of the hydroxy group for R₃ in the resultingcompound of formula (II) into a C₁₋₆ alkoxy or C₁₋₇ acyloxy group may becarried out as described hereinbefore in relation to the correspondingconversion of R₃ in a compound of formula (I).

A compound of formula (II) wherein R₃ is hydrogen may be prepared byknown methods, for example as described in Khim. Geterot. Soed 5(3),434, 1969.

A compound of formula (V) may be prepared by reacting a compound offormula (VIII): ##STR5## wherein R₁ and R₂ are as hereinbefore defined,the bromine atom being trans to the hydroxy group, with a base, such aspotassium hydroxide, in a solvent, such as ether or aqueous dioxan.

A compound of formula (VIII) may be prepared by reacting a compound offormula (IX): ##STR6## wherein R₁ and R₂ are as hereinbefore defined,with N-bromosuccinimide in a solvent, such as aqueous dimethylsulphoxide.

A compound of formula (IX) may be prepared in accordance with analogousprocesses to those described in the aforementioned European Patentpublications, i.e. by the process depicted below: ##STR7##

As mentioned previously, some of the compounds of formula (I) may existin optically active forms, and the processes of the present inventionproduce mixtures of such forms. The individual enantiomers may beresolved by conventional methods.

It is preferred that the compounds of formula (I) are isolated inpharmaceutically acceptable form.

The intermediates of formulae (II) represent part of the presentinvention. The intermediates of formulae (III), (IV), (V), (VI), (VII),(VIII) and (IX) are known or may be prepared in accordance with anappropriate known process.

As mentioned previously, the compounds of formula (I) have been found tohave blood-pressure lowering activity. They are therefore useful in thetreatment of hypertension. They are also believed to be of potential usein the treatment of other disorders hereinbefore referred to.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. Inparticular, the present invention provides an anti-hypertensivepharmaceutical composition which comprises an anti-hypertensiveeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample parenteral administration for patients suffering from heartfailure. Other alternative modes of administration include sublingual ortransdermal administration. A composition may be in the form of spray,aerosol or other conventional method of inhalation, for treatingrespiratory tract disorders.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations, such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavoring or coloringagents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration.

The present invention further provides a method of prophylaxis ortreatment of hypertension in mammals including man, which comprisesadministering to the suffering mammal an anti-hypertensive effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

An effective amount will depend on the relative efficacy of thecompounds of the present invention, the severity of the hypertensionbeing treated and the weight of the sufferer. However, a unit dose formof a composition of the invention may contain from 1 to 100 mg of acompound of the invention and more usually from 1 to 50 mg, for example1 to 25 mg such as 1, 2, 5, 10, 15 or 20 mg. Such compositions may beadministered from 1 to 6 times a day, more usually from 1 to 4 times aday, in a manner such that the daily dose is from 1 to 200 mg for a 70kg human adult and more particularly from 1 to 100 mg.

No toxicological effects are indicated at the aforementioned dosageranges.

The present invention further provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment orprophylaxis of hypertension.

The following descriptions relate to the preparation of intermediatesand the following example relates to the preparation of a compound offormula (I).

All temperatures therein are in ° C.

DESCRIPTION 1 2,2-Dimethyl-6-t-butyl-2H-1-benzopyran (D1) ##STR8##

4-t-Butylphenol (10 g) and sodium hydroxide (3.99 g) were added to astirred mixture of water (60 ml) and dichloromethane (60 ml) followed bybenzyltrimethylammonium hydroxide (40% solution in methanol, 150 ml) and3-chloro-3-methyl-butyne (13.65 g). After stirring at ambienttemperature for 11 days, the layers were separated and the aqueous layerextracted with chloroform. The combined organic extracts wereconcentrated in vacuo and the residue dissolved in diethyl ether. Thesolution was washed with water, 10% sodium hydroxide solution, thenbrine, and dried over magnesium sulphate. Removal of drying agent andsolvent gave 3-methyl-3-(4-t-butylphenoxy)-but-1-yne as a yellow oil(13.35 g).

A solution of this product in ortho-dichlorobenzene (27 ml) was heatedunder reflux, under nitrogen, for 12 hours. Solvent was removed invacuo, and the residue chromatographed on silica gel eluted with ethylacetate: 60-80 petroleum ether (1:19) to give the desired chromene as abrown oil (3.4 g) having:

¹ H nmr (CDCl₃)

1.27 (s, 9H)

1.40 (s, 6H)

5.50 (d, J=9 Hz, 1H)

6.25 (d, J=9 Hz, 1H)

6.60 (d, J=8 Hz, 1H)

7.10 (m, 2H)

DESCRIPTION 2Trans-6-(t-butyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran(D2) ##STR9##

A solution of 2,2-dimethyl-6-t-butyl-2H-1-benzopyran (3.4 g) in dimethylsulphoxide (35 ml) and water (3 ml) was treated with N-bromosuccinimide(3.1 g) and the mixture stirred vigorously for 1 hours. Water was added,and the mixture extracted into ethyl acetate. The combined organicextracts were washed with water, then brine, and dried over magnesiumsulphate. Removal of drying agent and solvent gave the requiredbromohydrin (0.88 g) having

M.pt. 122°-3° C.

¹ H nmr (CDCl₃)

1.30 (s, 9H)

1.40 (s, 3H)

1.58 (s, 3H)

2.44 (d, J=6 Hz, 1H)

4.14 (d, J=10 Hz, 1H)

4.90 (dd, J=10,6 Hz, 1H)

6.73 (d, J=9 Hz, 1H)

7.25 (dd, J=9,3 Hz, 1H)

7.48 (d, J=3 Hz, 1H)

Mass spectrum: Found M⁺ 312.0723; C₁₅ H₂₁ O₂ Br requires M⁺ 312.0725

DESCRIPTION 36-t-Butyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (D3)##STR10##

A mixture oftrans-6-t-butyl-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran(0.88 g) and potassium hydroxide pellets (0.88 g) in dry diethyl ether(88 ml) was stirred vigorously for 4 days. Filtration and removal ofsolvent in vacuo gave the desired epoxide as a brown oil (0.52 g) having

¹ H nmr (CDCl₃)

1.20 (s, 3H)

1.30 (s, 9H)

1.55 (s, 3H)

3.40 (d, J=4 Hz, 1H)

3.80 (d, J=4 Hz, 1H)

6.60 (d, J=9 Hz, 1H)

7.13 (dd, J=9,3 Hz, 1H)

7.20 (d, J=3 Hz, 1H)

Mass spectrum: Found M⁺ 232.1463; C₁₅ H₂₀ O₂ requires M⁺ 232.1465.

DESCRIPTION 4 2,2-Dimethyl-6-i-propyl-2H-1-benzopyran (D4) ##STR11##

The title compound (2.2 g) was prepared from 4-i-propyl phenol (9.07 g)as in Description 1.

¹ H nmr (CDCl₃)

1.20 (d, J=7 Hz, 6H)

1.40 (s, 6H)

2.80 (septet, 1H)

5.45 (d, J=10 Hz, 1H)

6.20 (d, J=10 Hz, 1H)

6.70-7.30 (m, 3H)

DESCRIPTION 5Trans-6-(i-propyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran(D5) ##STR12##

2,2-Dimethyl-6-i-propyl-2H-1-benzopyran (2.2 g) was reacted as inDescription 2 to give the title compound (2.7 g) as an oil having

¹ H nmr (CDCl₃)

1.20 (d, J=7 Hz, 6H)

1.37 (s, 3H)

1.55 (s, 3H)

2.80 (septet, J=7 Hz, 1H)

4.03 (d, J=9 Hz, 1H)

4.80 (m, 1H)

6.55 (d, J=8 Hz, 1H)

6.80-7.20 (m, 2H)

Mass spectrum: Found M⁺ 298.0563, 300.0553; C₁₄ H₁₉ O₂ Br requires298.0568, 300.0548

DESCRIPTION 6Trans-6-(i-propyl)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran(D6) ##STR13##

Trans-6-(i-propyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran(2.7 g) was reacted as in Description 3 to give the title compound (1.89g) as a pale brown oil having

¹ H nmr (CDCl₃)

1.20 (a, J=7 Hz, 6H)

1.20 (s, 3H)

1.50 (s, 3H)

2.80 (septet, J=7 Hz, 1H)

3.40 (d, J=4 Hz, 1H)

3.80 (d, J=4 Hz, 1H)

6.60 (d, J=8 Hz, 1H)

6.80-7.30 (m, 2H)

Mass spectrum: Found M⁺ 218.1325; C₁₄ H₁₈ O₂ requires 218.1307

DESCRIPTION 7trans-4-Amino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol (D7)##STR14##

A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (7g, see J. Med. Chem. 26, 1582, 1983) in concentrated ammonia solution(90 ml) and ethanol (160 ml) was stirred at room temperature for 5 days.Evaporation of solvent gave the title compound (7 g) as a crude solidwhich was used directly, without purification.

NMR (CDCl₃) δ

1.15 (s, 3H)

1.38 (s, 3H)

2.25 (s, 3H)

3.23 (d, J=9 Hz, 1H)

3.57 (d, J=9 Hz, 1H)

6.68 (d, J=8 Hz, 1H)

6.87 (q, J=8,2 Hz, 1H)

7.02 (narrow m, 1H)

DESCRIPTION 8trans-4-Amino-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol(D8) ##STR15##

The epoxide of description 6 (2.5 g) was stirred in ethanol (125 ml) and0.88 ammonia solution (120 ml) at room temperature for 20 h. Thesolution was evaporated and partitioned between ethyl acetate and water.The organic layer was washed with brine and dried over anhydrousmagnesium sulphate, filtered and evaporated to give the title compound(1.49 g) which was used directly.

NMR (CDCl₃) δ

1.17 (s, 3H)

1.20 (d, J=6 Hz, 6H)

2.43 (m, 3H, exchangeable with D₂ O) overlapped with 2.80 (m, J=6 Hz, 5lines visible, 1H)

3.28 (d, J=9 Hz, 1H)

3.61 (d, J=9 Hz, 1H)

6.59 (d, J=8 Hz, 1H)

6.92 (q, J=8,2 Hz, 1H)

7.05 (narrow m, 1H)

DESCRIPTION 9 6-Ethyl-2,2-dimethyl-2H-1-benzopyran (D9) ##STR16##

To 4-ethylphenol (8.15 g) and sodium hydroxide pellets (3.99 g) stirredin dichloromethane (60 ml) and water (60 ml) was addedbenzyltrimethylammonium hydroxide (40% solution in methanol, 150 ml) and3-chloro-3-methyl-butyne (13.65 g). The reaction mixture was stirred atroom temperature for 2 weeks. The layers were separated, and the aqueouslayer extracted with chloroform. The combined organic extracts wereevaporated, and the residue taken up in ether and washed with 5Nhydrochloric acid, 10% aqueous sodium hydroxide, water, and brine anddried over anhydrous magnesium sulphate. Removal of drying agent andsolvent gave an oil (9.9 g) which was refluxed in NN-diethylaniline (50ml) under nitrogen for 2.75 h. The mixture was cooled, and poured intocooled 5N hydrochloric acid (100 ml) and the solution extracted withether. The organic phase was washed with 5N hydrochloric acid and brineand dried over anhydrous magnesium sulphate. Removal of drying agent andsolvent left a brown oil (9.0 g) which was chromatographed on silica geland eluted with 5% ethyl acetate-pentane to give the title benzopyran(2.36 g) as an oil.

Mass spectrum (EI) M⁺ at m/z 188.1192.

C₁₃ H₁₆ O requires 188.1201.

DESCRIPTION 10trans-3-Bromo-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol(D10) ##STR17##

To a solution of 6-ethyl-2,2-dimethyl-2H-1-benzopyran (2.36 g) indimethyl sulphoxide (20 ml) and water (2 ml) was addedN-bromosuccimimide (2.46 g) and the mixture stirred for 1.5 h. Water wasadded and the mixture extracted with ethyl acetate. The organic extractwas washed with water, brine and dried over anhydrous magnesiumsulphate. Removal of drying agent and solvent left the title bromonydrinas a brown oil (3.0 g)

NMR (CDCl₃ +D₂ O)

1.22 (t, J=7 Hz, 3H)

1.40 (s, 3H)

1.60 (s, 3H)

2.58 (q, J=7 Hz, 2H)

4.14 (d, J=9 Hz, 1H)

4.91 (d, J=9 Hz, 1H)

6.72 (d, J=8 Hz, 1H)

6.95-7.40 (m, 2H)

DESCRIPTION 11 3,4-Epoxy-6-ethyl-3,4-dihydro-2H-1-benzopyran (D11)##STR18##

The bromohydrin of description 10 (3.0 g) and potassium hydroxidepellets (3.1 g) were stirred vigorously in diethyl ether (500 ml) for 6days at room temperature. Filtration and evaporation gave the titleepoxide (1.91 g) as a brown oil, which was used directly in example 13.

DESCRIPTION 12 2,2-Dimethyl-6-cyclopentyl-2H-1-benzopyran (D12)##STR19##

4-Cyclopentylphenol (10.0 g), and sodium hydroxide pellets (3.7 g) werestirred in water (60 ml) and dichloromethane (60 ml).Benzyltrimethylammonium hydroxide (75 ml, 40% solution in methanol) wasadded to the solution, followed by 3-chloro-3-methylbutyne (12.63 g) andthe reaction mixture stirred under reflux condenser, with sonication.The layers were separated, and the aqueous phase extracted withchloroform. The combined organic layers were evaporated, and the residuetaken up in ether. The ether solution was washed with 10% sodiumhydroxide solution, and brine and dried over anhydrous magnesiumsulphate. Filtration and evaporation gave a pale brown oil (10.89 )which was refluxed in o-dichlorobenzene (22 ml) under nitrogen for 2 h.Evaporation and chromatography of the resulting brown oil (9.3 g) gavethe title benzopyran (4.18 g).

NMR (CDCl₃) δ

1.42 (s, 6H)

1.47-1.86 (m, 6H)

2.03 (m, 2H)

2.90 (m, 1H)

5.57 (d, J=10 Hz, 1H)

6.28 (d, J=10 Hz, 1H)

6.68 (d, J=8 Hz, 1H)

6.83 (d, J=2 Hz, 1H)

6.97 (q, J=8,2 Hz, 1H)

DESCRIPTION 13trans-3-Bromo-3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran-4ol(D13) ##STR20##

To the benzopyran of description 12 (4.08 g) in dimethyl sulphoxide (40ml) and water (4 ml) was added N-bromosuccinimide (3.49 g) and thereaction mixture stirred at room temperature for 2 h. before theaddition of further N-bromosuccinimide (0.35 g), and an additional 0.5 hof stirring. Extraction via ethyl acetate yielded a yellow solid (5.36g) which was used directly to form the epoxide of description 14.

Mass spectrum (EI) M⁺ at m/z 324.0727.

C₁₆ H₂₁ O₂ Br requires 324.0726.

DESCRIPTION 143,4-Epoxy-3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran (D14)##STR21##

The bromohydrin of description 13 (5.0 g) and potassium hydroxidepellets (5.0 g) were vigorously stirred in ether (500 ml) at roomtemperature for 6 days. Filtration and evaporation gave the epoxide ofthis description as a pale brown oil (3.12 g).

NMR (CDCl₃) δ

1.24 (s, 3H)

1.56 (s, 3H)

1.52-1.86 (series of m, 6H)

2.04 (m, 2H)

2.93 (symmetrical m, 1H)

3.47 (d, J=4 Hz, 1H)

3.87 (d, J=4 Hz, 1H)

6.72 (d, J=8 Hz, 1H)

7.09 (q, J=8,2 Hz, 1H)

7.18 (d, J=2 Hz, 1H)

EXAMPLE 1trans-6-Methyl-2,2-dimethyl-4-(2-oxopiperidinyl)-2H-1-benzopyran-3-ol(E1) ##STR22##

2-Piperidone (1.0 g) was added to a stirred suspension of sodium hydride(300 mg) in dry dimethylsulphoxide (20 ml) and the mixture stirred for 1hour, under nitrogen. Then a solution of6-methyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.9 g) indimethylsulphoxide (10 ml) was added and the mixture stirred for 16hours, at room temperature. Water was added, and the mixture extractedinto ethyl acetate. The combined organic extracts were washed withwater, then brine, and dried over magnesium sulphate. Removal of solventin vacuo, and recrystallisation of the residue from ethyl acetate:60°-80° petroleum-ether (1:9) gave the title compound as colorlessprisms (400 mg, 15%) having m.p. 162°-4° C.;

¹ H n.m.r. (CDCl₃)

1.25 (s,3H)

1.50 (s,3H)

1.80 (m,4H)

2.25 (s,3H)

2.60 (t,J=8 Hz,2H)

3.00 (m,2H)

3.60 (br s,OH)

3.75 (d,J=10 Hz,1H)

5.85 (d,J=10 Hz,1H)

6.80 (m,3H)

Anal. Found: C 70.53%, H 8.13%, N 4.88%; C₁₇ H₂₃ NO₃ requires: C 70.56%,H 8.01%, N 4.84%.

EXAMPLE 2trans-6-t-Butyl-2,2-dimethyl-4-(2-oxo-pyrrolidinyl)-2H-1-benzopyran-3-ol(E2) ##STR23##

An 80% dispersion of sodium hydride in oil (0.067 g) was added to astirred solution oftrans-6-t-butyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.52g) and 2-pyrrolidinone (0.19 g) in dry dimethyl sulphoxide (25 ml), andthe mixture stirred for 20 hours under nitrogen. Water was added, andthe mixture extracted into ethyl acetate. The combined organic extractswere washed with water, then brine, and dried over magnesium sulphate.Removal of solvent in vacuo and recrystallisation of the residue fromethyl acetate/60-80 petroleum ether gave the title compound as finewhite needles (0.11 g) having

M.pt. 227°-8° C.

¹ H nmr (CDCl₃)

1.25 (s, 9H)

1.27 (s, 3H)

1.49 (s, 3H)

1.95-2.20 (m, 2H)

2.57 (m, 2H)

3.00-3.15 (m, 2H)

3.20-3.30 (m, 1H)

3.73 (dd, J=11,6 Hz, 1H)

5.30 (d, J=11 Hz, 1H)

6.75 (d, J=9 Hz, 1H)

6.90 (d, J=3 Hz, 1H)

7.20 (dd, J=9,3 Hz, 1H)

Mass spectrum: Found M⁺ 317.1992; C₁₉ H₂₇ NO₃ requires 317.1991

Analysis: Found C, 71.46; H, 8.43; N, 4.17; C₁₉ H₂₇ NO₃. requires C,71.89; H, 8.57; N, 4.41.

EXAMPLE 3trans-6-(i-Propyl)-2,2-dimethyl-4-(2-oxo-pyrrolidinyl)-2H-1-benzopyran-3-ol(E3) ##STR24##

Trans-6-(i-propyl)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran(1.89 g) reacted as in Example 2 to give the title compound (0.31 g) asfine white needles having

M.pt. 167°-173° C.

¹ H nmr (CDCl₃)

1.19 (d, J=7 Hz, 6H)

1.26 (s, 3H)

1.49 (s, 3H)

2.10 (m, 2H)

2.58 (m, 2H)

2.80 (septet, J=7 Hz, 1H)

2.95 (d, J=6 Hz, 1H)

3.10 (m, 1H)

3.25 (m, 1H)

3.75 (dd, J=10,6 Hz, 1H)

5.28 (d, J=10 Hz, 1H)

6.75 (m, 2H)

7.04 (dd, J=9,3 Hz, 1H)

Mass spectrum: Found M⁺ 303.1843; C₁₈ H₂₅ NO₃ requires 303.1835

Analysis: Found C, 71.43, 71.12; H, 8.54, 8.43; N, 4.59, 4.58; C₁₈ H₂₅NO₃ requires C, 71.26; H, 8.31; N, 4.62

EXAMPLE 4trans-3,4-Dihydro-2,2,6-trimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol(E4) ##STR25##

2-Pyrrolidone (1.02 g) was added to a suspension of sodium hydride (0.3g, 80% dispersion in oil) in dry dimethyl sulphoxide (20 ml) undernitrogen at room temperature, and the mixture stirred for 1 h. Asolution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran in drydimethyl sulphoxide (10 ml) was then added, and the reaction mixturestirred for an additional 16 h. Cautious addition of water andextraction via ethyl acetate gave a crude product (1.84 g) which waschromatographed on silica gel and eluted with 60°-80° C. petroleumether-ethyl acetate mixtures to give a foam (0.7 g) which wasrecrystallised from 60°-80° C. petroleum ether-ethyl acetate (0.53 g).Two further recrystallisations from ethyl acetatepentane gave theanalytical sample of the title compound mp 187°-188° C.

Analysis: Found C,70.01; H,8.10; N,4.83. C₁₆ H₂₁ NO₃ requires C,69.79;H,7.69; N,5.09.

EXAMPLE 5trans-3,4-Dihydro-2,2,6-trimethyl-4-[N,N-dimethyl-2-acetamido]-2H-1-benzopyran(E5) ##STR26##

A solution of lithium diisopropylamine in tetrahydrofuran (20 ml) wasprepared at -20° from n-butyl lithium (6.7 ml, 1.5M soln. in hexane) anddiisopropylamine (1.4 ml) under N₂. A solution of N,N-dimethylacetamide(0.87 g) in tetrahydrofuran (15 ml) was then added dropwise at -20° C.and the solution stirred for 0.5 h. A solution of3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (1.9 g) intetrahydrofuran (20 ml) was then added at 0° C. and the mixture allowedto attain room temperature and then refluxed for 2 h. After cooling, thereaction mixture was partitioned between ethyl acetate and dil. HCl, andthe organic layer washed with water, brine and then dried over anhydrousMgSO₄, filtered and evaporated, to give a white solid which wasrecrystallised from ethyl acetate-60°-80° C. petroleum ether (0.26 g) asan off-white solid m.p. 151°-153° C.

NMR (CDCl₃) δ

1.15 (s, 3H)

1.47 (s, 3H)

2.27 (s, 3H)

2.63 (q, J=17,10 Hz, 1H)

3.04 (s, 3H)

3.08 (s, 3H)

3.15 (q, J=17,2 Hz, 1H)

3.27 (t, J=10,9 Hz, 1H)

3.53 (q, J=9,3 Hz, 1H, collapsing to J=9 Hz on addition of D₂ O)

5.33 (d, J=3 Hz, 1H exchangeable with D₂ O)

6.73 (d, J=8 Hz, 1H)

6.93 (m, 2H)

EXAMPLE 6trans-4-Acetylamino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol(E6) ##STR27##

To the crude aminoalcohol of description 7 (1.0 g) in dichloromethane(60 ml) and triethylamine (0.47 ml) was added acetyl chloride (0.34 ml)dropwise, with stirring at room temperature. After the reaction mixturehad been stirred for an additional 3 h the organic phase was washed withwater and brine before drying over anhydrous MgSO₄. Filtration andevaporation and chromatography (chromatotron 30% pentane-EtOAc-EtOAc)and recrystallisation from EtOAc gave the title compound m.p. 188°-190°C.

EXAMPLE 7trans-3,4-Dihydro-2,2,6-trimethyl-2-(N-methylureido)-2H-1-benzopyran-3-ol(E7) ##STR28##

To the crude aminoalcohol of description 7 (1 g) dissolved indichloromethane (40 ml) was added methyl isocyanate (0.46 ml) during 5min with stirring at 0° C. After an additional 2 h at 0° C., thesolution was washed with water and brine and dried over anhydrous MgSO₄.Filtration and evaporation and chromatography (chromatotron CHCl₃ --10%MeOH--CHCl₃) gave a solid which was recrystallised from ethylacetate-60°-80° C. petroleum ether (450 mg). A further recrystallisationof a small amount gave the title compound as the 0.25 hydrate, m.p.170°-171° C.

NMR (CDCl₃) δ

1.22 (s, 3H)

1.43 (s, 3H)

2.25 (s, 3H)

2.79 (s, 3H)

3.51 (d, J=9 Hz, 1H)

4.74 (d, J=9 Hz, 1H)

6.63 (d, J=8 Hz, 1H)

6.93 (q, J=8,2 Hz, 1H)

7.03 (narrow m, 1H)

EXAMPLE 8trans-4-(4-Fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol(E8) ##STR29##

To the aminoalcohol of description 8 (1.45 g), and triethylamine (0.94ml) in dichloromethane (50 ml) cooled to 0° C. under nitrogen, was addedp-fluorobenzoyl chloride (0.8 ml). The mixture was stirred for a further10 min at 0° C. and for 16 h at room temperature, and then washed withwater containing a little sodium hydroxide solution, and brine. Theorganic layer was dried over anhydrous magnesium sulphate, filtered andevaporated and the crude solid recrystallised from ethyl acetate-60°-80°C. petroleum ether to give the compound of this example as a white solid(0.66 g) of mp 235°-236° C.

Mass spectrum M⁺ at m/z 357.1740.

C₂₁ H₂₄ NO₃ F requires 357.1750.

EXAMPLE 9trans-3,4-Dihydro-6-hydroxymethyl-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol(E9) ##STR30##

Totrans-6-Formyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran(0.5 g, described in J. Med. Chem. 29, 2194 (1986)) dissolved in ethanol(10 ml) and methanol (10 ml) cooled in an ice bath was added sodiumborohydride (65 mgm) under nitrogen, and the mixture stirred for 1.5 h.The solution was acidified to pH 3 with glacial acetic acid, and dilutedwith water (200 ml) and extracted with methylene chloride. The organiclayer was washed with brine and dried over anhydrous magnesium sulphate.Filtration and evaporation gave a foam (0.41 g) which was recrystallisedtwice from ethyl acetate-60°-80° C. petroleum ether to give the compoundof this example of mp 175°-178° C.

Mass spectrum (EI) M⁺ at m/z 291.1471.

C₁₆ H21O₄ N requires 291.1471.

EXAMPLE 10trans-6-Aminomethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol(E10) ##STR31##

trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol(5 g, prepared as described in J. Med. Chem. 29, 2194 (1986)), inethanol (375 ml) and glacial acetic acid (75 ml) containing concentratedHCl (5 ml) was shaken in the presence of 10% Pd/C (1 g) in an atmosphereof hydrogen for 4 h. The catalyst was filtered off and the solutionneutralised with 10% aqueous NaOH solution, and the solution evaporatedto dryness. Acid-base extraction, and drying of a dichloromethanesolution of the residue, furnished, after recrystallisation from ethylacetate-pentane, 2.03 g of the required aminomethyl compound of example4 of mp 191°-193° C. as the hemihydrate.

NMR (CD₃)₂ SO δ

1.14 (s, 3H)

1.41 (s, 3H)

1.95 (m, 2H)

2.39 (m, 2H)

2.88 (m, 1H)

3.28 (m, 3H including 2H exchangeable with D₂ O)

3.58 (s, 2H)

3.64 (d, J=10 Hz, 1H)

4.97 (d, J=10H, 1H)

5.53 (m, 1H exchangeable with D₂ O)

6.70 (d, J=8 Hz, 1H)

6.81 (narrow m, 1H)

7.09 (q, J=8,2 Hz, 1H)

EXAMPLE 11trans-6-Acetylaminomethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol(E11) ##STR32##

To the compound of example 10 (0.57 g) and triethylamine (0.55 ml)stirred in dichloromethane (50 ml) was added acetyl chloride (0.154 ml)dropwise, at 0° C. After 2 h at 0° C., more acetyl chloride (0.154 ml)was added and the reaction mixture stirred for a further 16 h andallowed to attain room temperature. The organic phase was washed withwater and brine and dried over anhydrous magnesium sulphate. Filtrationand evaporation gave the crude product (0.33 g) which was recrystallisedfrom ethyl acetate-dichloromethane to give the title compound (0.24 g)as colorless crystals of mp 206°-208° C.

Mass spectrum (EI) M⁺ at m/z 332.1735.

Calcd. for C₁₈ H₂₄ N₂ O₄ 332.1745.

EXAMPLE 12trans-6-(N,N-dimethylaminomethyl)-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-benzopyran-3-ol(E12) ##STR33##

A solution oftrans-6-(aminomethyl)-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-benzopyran-3-ol(0.828 g, example 10) and aqueous formaldehyde solution (37/40% w/v) (3ml) in methanol (10 ml) was heated under reflux, with stirring, for 30min. After cooling to ice-bath temperature, sodium borohydride (0.4 g)was added portionwise. After stirring for 1 h at room temperature, thereaction mixture was evaporated in vacuo to give a cloudy oil. Water wasadded, and the mixture extracted into chloroform. The organic extractswere washed with brine and dried over anhydrous sodium sulphate, and thesolvent evaporated in vacuo to give an oil. Column chromatography(Kieselgel 60, eluting with chloroform-methanol) gave a colorless oil(0.5 g). The oil was dissolved in the minimum ethyl acetate and allowedto stand overnight. The crystals which formed were filtered off andrecrystallised from ethyl acetate to give the title compound as finewhite needles (0.25 g) having m.p. 156°-7° C.

¹ H nmr (CDCl₃) δ

1.26 (s, 3H)

1.49 (s, 3H)

1.94-2.16 (m, 2H)

2.23 (s, 6H)

2.50-2.63 (m, 2H)

3.01 (br.s, 1H)

3.06-3.17 (m, 1H)

3.18-3.32 (m, 1H)

3.37 (s, 2H)

3.75 (d, J=10 Hz, 1H)

5.28 (d, J=10 Hz, 1H)

6.79 (d, J=8 Hz, 1H)

6.86 (d, J=2 Hz, 1H)

7.12 (d.d., J=8,2 Hz, 1H)

Mass spectrum: Found M⁺ 318.1955;

C₁₈ H₂₆ N₂ O₃ requires 318.1944.

Analysis: Found C,67.73; H,8.09; N,8.59. C₁₈ H₂₆ N₂ O₃ requires C,67.90;H,8.23; N,8.80.

EXAMPLE 13trans-6-Ethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol(E13) ##STR34##

To a mixture of pyrrolidone (0.416 g) and sodium hydride (0.146 g, 80%dispersion in oil) in dimethyl sulphoxide (50 ml) was added the epoxideof description 11 (1.0 g). The mixture was stirred at room temperatureunder nitrogen for 4 h. Cautious addition of water and extraction viaethyl acetate gave an oil which was purified on the chromatotron (20%ethyl acetate -60°-80° C. petroleum ether-ethyl acetate) to give thecompound of example 13 after recrystallisation from ethylacetate-60°-80° C. petroleum ether as crystals of mp 154°-163° C.

Mass spectrum (EI) M⁺ at m/z 289.1683.

C₁₇ H₂₃ NO₃ requires 289.1678.

EXAMPLE 14trans-3,4-Dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-6-cyclopentyl-2H-1-benzopyran-3-ol(E14) ##STR35##

To the epoxide of description 14 (1.5 g) dissolved in dimethylsulphoxide (15 ml) was added pyrrolidone (0.404 g) with stirring undernitrogen. Sodium hydride (0.142 g, 80% dispersion in oil) was added tothe mixture which was stirred for 18 h. Cautious addition of water andextraction via ethyl acetate gave the title compound (0.55 g) afterrecrystallisation from ethyl acetate-pentane m.p. 179°-184° C.

Mass spectrum (EI) M⁺ at m/z 329.1993.

C₂₀ H₂₇ NO₃ requires 329.1991.

EXAMPLE 15trans-2,2-Dimethyl-6-(1,3-dioxo-2-isoindoline)methyl-4-(2-oxopyrrolinyl)-2H-1-benzopyran-3-ol##STR36##

A mixture oftrans-6-(aminomethyl)-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-penzopyran-3-ol(0.68 g example 10), N-carboethoxy-phthalimide (0.62 g) and sodiumbicarbonate (0.414 g) in water (5 ml) was stirred for 17 h at roomtemperature. The white solid was removed by filtration, washed withwater and dried in vacuo. Recrystallisation from chloroform/ethylacetate gave the title compound as a white solid (0.74 g), having m.p.220°-221.5° C.

¹ H-nmr (CDCl₃) δ

1.24 (s, 3H)

1.47 (s, 3H)

2.01-2.18 (m, 2H)

2.47-2.70 (m, 2H)

3.01-3.13 (m, 1H)

3.13-3.26 (m, 2H)

3.7 (dd J=10, 4 Hz, 1H)

4.66 (d, J=14 Hz, 1H)

4.81 (d, J=14 Hz, 1H)

5.26 (d, J=10 Hz, 1H)

6.76 (d, J=8 Hz, 1H)

7.03 (d, J=2 Hz, 1H)

7.24 (dd, J=8,2 Hz, 1H)

7.66-7.75 (m, 2H)

7.78-7.88 (m, 2H)

Mass spectrum: Found M⁺ 420.1682.

C₂₄ H₂₄ N₂ O₅ requires 420.1685.

Analysis: Found C,68.45; H,5.75; N,6.57.

C₂₄ H₂₄ N₂ O₅ requires C,68.56; H,5.75; N,6.66.

EXAMPLE 16 4-Chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran(E16) ##STR37##

To a solution of 4-amino-3,4-dihydro-2,2,6-dimethyl-2H-1-benzopyran(1.63 g, described in Khim. Geterot. Soed. 5(3), 434, 1969) in 40 mldichloromethane at 0° C. was added triethylamine (1.2 ml) followed bychloroacetyl chloride (0.96 g). The solution was stirred for 16 n thenwashed with saturated brine solution, separated, dried (MgSO₄) andconcentrated to a cream solid. Chromatography (silica, CH₂ Cl₂ eluent)provided 4-chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran(1.78 g, 78%) as a white solid. m.p. 147°-148° C.

NMR (CDCl₃) δ

1.3 (s, 3H)

1.4 (s, 3H)

1.75 (d.d., J=13.2, 10.7 Hz, 1H)

2.25 (d.d., J=13.2, 6.6 Hz, 1H)

2.3 (s, 3H)

4.15 (ABq, J=15.6 Hz, 2H)

5.25 (d.d., J=10.7, 6.6 Hz, 1H)

6.8 (br d, J=8 Hz, 1H)

7.0 (m, 2H).

PHARMACOLOGICAL DATA Antihypertensive Activity

Systolic blood pressures were recorded by a modification of the tailcuff method described by I. M. Claxton, M. G. Palfreyman, R. H. Poyser,R. L. Whiting, European Journal of Pharmacology, 37,179 (1976). A W+W BPrecorder, model 8005 was used to display pulses. Prior to allmeasurements rats were placed in a heated environment (33.5°±0.5° C.)before transfer to a restraining cage. Each determination of bloodpressure was the mean of at least 6 readings. Spontaneously hypertensiverats (ages 12-18 weeks) with systolic blood pressures >180 mmHg wereconsidered hypertensive.

The compound of Example 1 gave a maximum fall in blood pressure of 33±2%at a dose of 1.0 mg/kg po.

The compound of Example 13 gave a maximum fall in blood pressure of54±2% at a dose of 1.0 mg/kg po. Other compounds of the Examples, suchas E2, E3 and E14 showed significant falls in blood pressure at a doseof 1.0 mg/kg po.

We claim:
 1. A compound of the formula ##STR38## wherein: one of R₁ andR₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₁ and R₂together are C₂₋₅ polymethylene; R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇alkylcarbonyloxy; R'₄ is ethyl, isopropyl, t-butyl or cyclopentyl, andR¹ ₆ is hydrogen or C₁₋₆ alkyl; the R¹ ₆ NH group being trans to the R₃group in formula (II) and the bromine atom being trans to the hydroxygroup in formula (VIII); provided that in formula (IX) R'₄ is not ethyl.2. The compound according to claim 1, which is2,2-dimethyl-6-t-butyl-2H-benzopyran.
 3. The compound according to claim1, which istrans-6-(t-butyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran.4. The compound according to claim 1, which is2,2-dimethyl-6-i-propyl-2H-1-benzopyran.
 5. The compound according toclaim 1, which istrans-6-(i-propyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran.6. The compound according to claim 1, which istrans-4-amino-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3o1.7. The compound according to claim 1, which istrans-3-bromo-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-o1. 8.The compound according to claim 1, which is2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran.
 9. The compound according toclaim 1, which istrans-3-bromo-3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran-4-o1.10. The compound according to claim 1 where R₁ and R₂ are both C₁₋₄alkyl.